In this application for competing renewal, we request funding for five years to complete the first adequately powered, placebo (PBO) controlled randomized clinical trial evaluating the efficacy of continuation phase cognitive therapy (C-CT) and fluoxetine (FLX) in outpatients with recurrent Major Depressive Disorder (MDD) who are at high risk for relapse. The trial is being conducted at The University of Texas Southwestern Medical Center and The University of Pittsburgh School of Medicine. "Higher risk" is defined by incomplete remission during the final weeks of acute phase CT, while "lower risk" is defined as a complete and stable remission. This trial has great public health significance because it will help clinicians to identify those patients at greatest risk for relapse who warrant longer courses of treatment. Such empirically-based decision rules could lower the cost of care by providing enough treatment for a depressive episode without either "over-treating" patients at lower risk or "under-treating" those patients at higher risk. This study is the first to evaluate continuation phase pharmacotherapy (FLX) after incomplete remission with acute phase CT. Further, the pharmacotherapy group will permit tests of mode-specific vs. non-specific therapeutic activity. Dependent variables measure response, relapse, recurrence, remission, and recovery. Blind evaluations and survival analyses are planned. A total of 288 new patients will be enrolled in years 06-09 of this competing renewal (Total n=724). Based on results of a planned (blinded) interim analysis, the study will either continue to completion as a three-arm trial (105 patients per arm) or will shift allocation of subjects from year 06 onward into the two active treatment arms (129 patients per arm). This modification has been made to maximize the statistical power for comparisons of C-CT and FLX therapies, without undermining the test efficacy of C-CT versus PBO. Based on results obtained to date (i.e., C-CT 8% relapse, PBO estimate approximately 24% relapse), the interim analysis will determine if more subjects are needed to answer the primary question (i.e., C-CT versus control) or if efforts can be shifted to comparing the relative merits of FLX relative to C-CT. Specifically, if C-CT is significantly more effective than PBO at the end of "Phase 1," then FLX must also have therapeutic activity.